Mixed cryoimmunoglobulins are cold-insoluble immune complexes most commonly of the type IgM (monoclonal)-IgG (heterogeneous). Their presence is associated with a wide variety of cardiovascular, renal, malignant, infectious and collagen disorders, as well as with no evidence of additional underlying disease (essential cryoglobulinemia). The relationship between the abnormal physical properties of these macromolecular complexes and clinical symptoms, however, is poorly understood. Proposed studies will focus on three aspects of mixed cryoglobulin phenomena in order to clarify the role of mixed cryoglobulins in disease processes: (1) characterization of the cryoprecipitation process, (2) the nature of the structural defect responsible for atypical solution behavior and (3) the interaction of mixed cryoglobulins with various surfaces. These studies will be based on our previous work with the simpler monoclonal cryoglobulins and will be primarily comparative in nature using monoclonal IgM and IgG and cold-soluble rheumatoid factor complexes as reference material. A large number of approaches will be employed in these analysis, including kinetic and equilibrium solution studies, spectroscopic, immunochemical and hydrodynamic measurement as well as novel applications of photoacoustic spectroscopy, two phase polymeric and organic systems, differential scanning calorimetry and reverse phase high performance liquid chromatography. As well as enhancing our understanding of cryoglobulin related disorders, important advances in our knowledge of the behavior of immune complexes should result from these studies.